Kinase-associated Endopeptidase 1 (Kae1) Participates in an Atypical Ribosome-associated Complex in the Apicoplast of Plasmodium falciparum

Mallari, Jeremy P.; Oksman, Anna; Vaupel, Barbara A.; Goldberg, Daniel E.

doi:10.1074/jbc.m114.586735

Cited by 15 publications

(15 citation statements)

References 30 publications

(14 reference statements)

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“…36 In the human malaria parasite Plasmodium falciparum, the cytoplasmic KAE1 gene appears to be essential. 37 Recent studies have shown that the absence of KAE1 also leads to strong phenotypes in multicellular organisms, such tissue-specific cell growth regulated by t 6 A in flies. 38,39 It is thus not surprising that a mutation that lowers t 6 A levels in humans even by 25% would lead to severe clinical phenotype, raising the possibility that Kae1 null could be embryonic lethal.…”

Section: Discussionmentioning

confidence: 99%

tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy

et al. 2017

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Post-transcriptional tRNA modifications are numerous and require a large set of highly conserved enzymes in humans and other organisms. In yeast, the loss of many modifications is tolerated under unstressed conditions; one exception is the N-threonyl-carbamoyl-adenosine (tA) modification, loss of which causes a severe growth phenotype. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with global developmental delay, failure to thrive and a renal defect manifesting in proteinuria and hypomagnesemia. Using exome sequencing, the patients were found to be homozygous for the c.974G>A (p.(Arg325Gln)) variant of the KAE1 gene. KAE1 is a constituent of the KEOPS complex, a five-subunit complex that catalyzes the second biosynthetic step of tA in the cytosol. The yeast KAE1 allele carrying the equivalent mutation did not rescue the tA deficiency of the kae1Δ yeast strain as efficiently as the WT allele; furthermore, tA levels quantified by LC-MS/MS were lower in the kae1Δ strain which was complemented by the mutation than in the kae1Δ strain, which was complemented by the WT allele. We conclude that homozygosity for c.974G>A (p.(Arg325Gln)) in KAE1 likely exerts its pathogenic effect by perturbing tA synthesis, thereby interfering with global protein production. This is the first report of tA biosynthesis defect in human. KAE1 joins the growing list of cytoplasmic tRNA modification enzymes, all associated with severe neurological disorders.

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Section: Discussionmentioning

confidence: 99%

tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy

et al. 2017

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“…Immunoblotting suggested that GCP1 was specific to mitochondria and absent in plastids (Haussuehl et al, 2009). It remains to be determined if this function is also required within plastids, which we suspect it is because this function is required in apicoplasts (Mallari et al, 2014). Plastid stromal DEG2 (#45) connects module III and IV and shares two coexpressors with DAP2 (AT3G29185 and AT3G62000; both encoding for plastid proteins).…”

Section: Connections Between Modules I To Ivmentioning

confidence: 99%

The Plastid and Mitochondrial Peptidase Network in Arabidopsis thaliana: A Foundation for Testing Genetic Interactions and Functions in Organellar Proteostasis

et al. 2017

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Plant plastids and mitochondria have dynamic proteomes. Protein homeostasis in these organelles is maintained by a proteostasis network containing protein chaperones, peptidases, and their substrate recognition factors. However, many peptidases, as well as their functional connections and substrates, are poorly characterized. This review provides a systematic insight into the organellar peptidase network in We present a compendium of known and putative Arabidopsis peptidases and inhibitors, and compare the distribution of plastid and mitochondrial peptidases to the total peptidase complement. This comparison shows striking biases, such as the (near) absence of cysteine and aspartic peptidases and peptidase inhibitors, whereas other peptidase families were exclusively organellar; reasons for such biases are discussed. A genome-wide mRNA-based coexpression data set was generated based on quality controlled and normalized public data, and used to infer additional plastid peptidases and to generate a coexpression network for 97 organellar peptidase baits (1742 genes, making 2544 edges). The graphical network includes 10 modules with specialized/enriched functions, such as mitochondrial protein maturation, thermotolerance, senescence, or enriched subcellular locations such as the thylakoid lumen or chloroplast envelope. The peptidase compendium, including the autophagy and proteosomal systems, and the annotation based on the MEROPS nomenclature of peptidase clans and families, is incorporated into the Plant Proteome Database.

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“…falciparum contains 2 nuclear encoded homologs of Tcs3 (Table 3): a Tcs3 that is similar to the yeast Tcs3, and an apicoplast-targeting Tcs3b, that is similar to Tcs3, 60 but is phylogenetically distant from all known Tcs3 and from the bacterial TsaD (Thiaville and de Cr ecy-Lagard, unpublished). Tcs3 interacts with both Tcs5 (Bud32) and Tcs7 (Cgi121), and Tcs3b interacts with multiple proteins associated with the apicoplast ribosome (Mallari and Goldberg, personal communication).…”

Section: Distribution Of the T 6 A Synthesis Genes Vary In Different mentioning

confidence: 99%

Diversity of the biosynthesis pathway for threonylcarbamoyladenosine (t⁶A), a universal modification of tRNA

2014

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Kinase-associated Endopeptidase 1 (Kae1) Participates in an Atypical Ribosome-associated Complex in the Apicoplast of Plasmodium falciparum

Cited by 15 publications

References 30 publications

tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy

tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy

The Plastid and Mitochondrial Peptidase Network in Arabidopsis thaliana: A Foundation for Testing Genetic Interactions and Functions in Organellar Proteostasis

Diversity of the biosynthesis pathway for threonylcarbamoyladenosine (t⁶A), a universal modification of tRNA

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Kinase-associated Endopeptidase 1 (Kae1) Participates in an Atypical Ribosome-associated Complex in the Apicoplast of Plasmodium falciparum

Cited by 15 publications

References 30 publications

tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy

tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy

The Plastid and Mitochondrial Peptidase Network in Arabidopsis thaliana: A Foundation for Testing Genetic Interactions and Functions in Organellar Proteostasis

Diversity of the biosynthesis pathway for threonylcarbamoyladenosine (t6A), a universal modification of tRNA

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Diversity of the biosynthesis pathway for threonylcarbamoyladenosine (t⁶A), a universal modification of tRNA